CN106831569B - Quinoline compound, preparation method thereof and application of quinoline compound as urate transporter inhibitor medicine - Google Patents

Quinoline compound, preparation method thereof and application of quinoline compound as urate transporter inhibitor medicine Download PDF

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CN106831569B
CN106831569B CN201611109936.3A CN201611109936A CN106831569B CN 106831569 B CN106831569 B CN 106831569B CN 201611109936 A CN201611109936 A CN 201611109936A CN 106831569 B CN106831569 B CN 106831569B
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compound
pharmaceutically acceptable
thio
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acceptable salt
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CN106831569A (en
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樊磊
杜武
李兴海
陈元伟
胥珂馨
陈锞
张少华
罗潼川
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Haichuang Pharmaceutical Co., Ltd
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Hinova Pharmaceuticals Inc
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • A61K31/47—Quinolines; Isoquinolines
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention discloses a quinoline compound, a preparation method thereof and application of the quinoline compound as a urate transporter inhibitor drug. The various compounds provided by the invention and salts, hydrates or solvates thereof are selective uric acid reabsorption inhibitors, can treat hyperuricemia and gout by promoting the excretion of uric acid from the body and reducing serum uric acid, and have the effect of reducing uric acid in animal bodies and human bodies.

Description

Quinoline compound, preparation method thereof and application of quinoline compound as urate transporter inhibitor medicine
Technical Field
The invention relates to quinoline compounds, a preparation method thereof and application of the quinoline compounds as urate transporter inhibitors.
Background
Urate transporter (URAT1) inhibitor can be used for treating hyperuricemia, gout, etc.
Disclosure of Invention
The invention provides a quinoline compound and application thereof as a urate transporter inhibitor drug.
The present invention provides a compound represented by the formula (A), or an optical isomer, solvate, pharmaceutically acceptable salt or prodrug thereof,
Figure BDA0001172277200000011
wherein:
z is selected from O, S or-NH-;
W1selected from N or CRa；W2Selected from N or CRb；W3Is selected fromN or CRc；
Ra、Rb、Rc、R2、R3Each independently selected from hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -ORd、-S(O)mRd、-C(O)Rd、C(O)ORd、-C(O)NReRf、-NReRfOr NReC(O)RfWherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl OR heteroaryl are each independently optionally further substituted with one OR more substituents selected from the group consisting of halogen, cyano, nitro, oxo, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -ORd、-S(O)mRd、-C(O)Rd、C(O)ORd、-C(O)NReRf、-NReRfOr NReC(O)RfSubstituted with the substituent(s);
Rdselected from hydrogen, halogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl each independently optionally further substituted with one or more groups selected from halogen, cyano, nitro, hydroxy, oxo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy, carboxylate, -C (O) NR ReRf、-NReRfOr NReC(O)RfSubstituted with the substituent(s);
Re、Rfeach independently selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl each independently optionally further substituted with one or more substituents selected from halogen, cyano, nitro, hydroxy, oxo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy, carboxylate; and m is 0, 1 or 2;
x, Y are each independently selected from hydrogen, halogen, cyano, nitro, alkyl, haloalkyl or hydroxyalkyl;
when Z is selected from O or S, R4Selected from hydrogen or alkyl or cycloalkyl; when Z is selected from-NH-, R4Selected from hydrogen, aryl or heteroaryl, preferably pyridyl.
Further, the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, has a structure represented by formula (I):
Figure BDA0001172277200000021
wherein R is1Selected from hydrogen, halogen, trifluoromethyl, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -ORd、-S(O)mRd、-C(O)Rd、C(O)ORd、-C(O)NReRf、-NReRfOr NReC(O)RfWherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl OR heteroaryl are each independently optionally further substituted with one OR more substituents selected from the group consisting of halogen, cyano, nitro, oxo, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -ORd、-S(O)mRd、-C(O)Rd、C(O)ORd、-C(O)NReRf、-NReRfOr NReC(O)RfSubstituted with the substituent(s);
R2、R3、R4、Rd、Re、Rfand m have the meanings given for formula (A).
Further, the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein:
R1selected from the group consisting of halogen, substituted or unsubstituted alkyl, trifluoromethyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl;
R2、R3each independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl;
R4selected from hydrogen or C1～C6Alkyl or C3～C6A cycloalkyl group of (a).
Further, the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein, when Z is selected from O, R is4Selected from hydrogen.
Further, the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein R is1Selected from the group consisting of halogen, trifluoromethyl, substituted or unsubstituted aryl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiadiazolyl or C3～C6A cycloalkyl group of (a).
Further, the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein R is1Selected from the group consisting of F, Br, Cl, trifluoromethyl, pyridyl, pyrimidinyl, pyrrolyl, imidazolyl, phenyl or cyclopropyl, wherein said phenyl is optionally further substituted with one or more substituents selected from the group consisting of methoxy, ethoxy, fluoro, chloro, bromo or trifluoromethyl.
Further, the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein R is2、R3Each independently selected from hydrogen, halogen or C1～C6Alkyl group of (1).
Further, the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof,
R2is selected from hydrogen and R3Is selected from methyl;
or, R2Is selected from hydrogen and R3Is selected from ethyl;
or, R2Is selected from hydrogen and R3Is selected from isopropyl;
or, R2And R3Are all selected from methyl;
or, R2And R3Are all selected from ethyl;
or, R2And R3Are all selected from n-propyl.
Further, the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, has a structure represented by formula (Ia):
Figure BDA0001172277200000031
wherein R is1Have the meaning stated in claim 2.
Further, the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein R is1Selected from the group consisting of halogen, trifluoromethyl, substituted or unsubstituted aryl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiadiazolyl or C3～C6A cycloalkyl group of (a).
Further, the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein R is1Selected from F, Br, Cl, trifluoromethyl, pyridylPyrimidinyl, pyrrolyl, imidazolyl, phenyl or cyclopropyl, wherein said phenyl is optionally further substituted with one or more substituents selected from methoxy, ethoxy, fluoro, chloro, bromo or trifluoromethyl.
Further, the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, has a structure represented by formula (Ib):
Figure BDA0001172277200000041
wherein R is1Have the meaning stated in claim 2.
Further, the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein R is1Selected from the group consisting of halogen, trifluoromethyl, substituted or unsubstituted aryl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiadiazolyl or C3～C6A cycloalkyl group of (a).
Further, the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein R is1Selected from the group consisting of F, Br, Cl, trifluoromethyl, pyridyl, pyrimidinyl, pyrrolyl, imidazolyl, phenyl or cyclopropyl, wherein said phenyl is optionally further substituted with one or more substituents selected from the group consisting of methoxy, ethoxy, fluoro, chloro, bromo or trifluoromethyl.
Further, the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, has a structure represented by formula (Ic):
Figure BDA0001172277200000051
wherein R is1Have the meaning stated in claim 2.
Further, the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein R is1Selected from the group consisting of halogen, trifluoromethyl, substituted or unsubstituted aryl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiadiazolyl or C3～C6A cycloalkyl group of (a).
Further, the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein R is1Selected from the group consisting of F, Br, Cl, trifluoromethyl, pyridyl, pyrimidinyl, pyrrolyl, imidazolyl, phenyl or cyclopropyl, wherein said phenyl is optionally further substituted with one or more substituents selected from the group consisting of methoxy, ethoxy, fluoro, chloro, bromo or trifluoromethyl.
Further, the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, has a structure represented by formula (Id) or (Ie):
Figure BDA0001172277200000052
wherein R is1Have the meaning stated in claim 2.
Further, the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein R is1Selected from halogen, trifluoromethyl, substituted or unsubstituted aryl,Substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiadiazolyl or C3～C6A cycloalkyl group of (a).
Further, the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein R is1Selected from the group consisting of F, Br, Cl, trifluoromethyl, pyridyl, pyrimidinyl, pyrrolyl, imidazolyl, phenyl or cyclopropyl, wherein said phenyl is optionally further substituted with one or more substituents selected from the group consisting of methoxy, ethoxy, fluoro, chloro, bromo or trifluoromethyl.
Further, the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein R is1Selected from cyclopropyl; r2And R3All have the meanings indicated in formula (A).
Further, the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein R is2、R3Each independently selected from hydrogen, halogen or C1～C6Alkyl group of (1).
Further, the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein R is1Is selected from pyridyl; r2And R3All have the meanings indicated in formula (A).
Further, the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein R is2、R3Each independently selected from hydrogen, halogen or C1～C6Alkyl group of (1).
Further, the compound, or light thereofA chemical isomer, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein R1Selected from phenyl substituted by one or two methoxy groups; r2And R3All have the meanings indicated in formula (A).
Further, the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein R is2、R3Each independently selected from hydrogen, halogen or C1～C6Alkyl group of (1).
Further, the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein R is1Is selected from Br; r2And R3All have the meanings indicated in formula (A).
Further, the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein R is2、R3Each independently selected from hydrogen, halogen or C1～C6Alkyl group of (1).
Further, the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein R is1Selected from fluorophenyl; r2And R3All have the meanings indicated in formula (A).
Further, the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein R is2、R3Each independently selected from hydrogen, halogen or C1～C6Alkyl group of (1).
Further, the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein R is1Selected from trifluoromethylphenyl; r2And R3All have the meanings indicated in formula (A).
Further, the compound, or an optical isomer, or a solvate, or a pharmaceutically acceptable salt thereofAn acceptable salt, or a prodrug thereof, wherein R2、R3Each independently selected from hydrogen, halogen or C1～C6Alkyl group of (1).
Further, the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, is one of the following compounds:
Figure BDA0001172277200000071
Figure BDA0001172277200000081
Figure BDA0001172277200000091
Figure BDA0001172277200000101
Figure BDA0001172277200000111
the invention also provides a preparation method of the compound, which comprises the following steps:
Figure BDA0001172277200000112
or, the method comprises the following steps:
Figure BDA0001172277200000113
the invention also provides application of the compound, or an optical isomer, a solvate or a prodrug thereof in preparing URAT1 inhibitor medicines.
Further, the drug is a drug for preventing and/or treating gout, recurrent gout attack, gouty arthritis, hyperuricemia, hypertension, cardiovascular disease, coronary heart disease, lesch-naphalene syndrome, kelley-seegmi syndrome, kidney disease, kidney stone, kidney failure, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis, or hypoxanthine-guanine phosphoribosyltransferase deficiency, preferably a drug for preventing and/or treating gout or hyperuricemia.
The invention also provides a pharmaceutical composition, which is a preparation prepared by taking the compound, or the optical isomer, the solvate, the pharmaceutically acceptable salt or the prodrug of the compound as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
The invention also provides application of the pharmaceutical composition in preparation of URAT1 inhibitor medicines.
Further, the medicament is a medicament for preventing and/or treating gout, recurrent gout attack, gouty arthritis, hyperuricemia, hypertension, cardiovascular disease, coronary heart disease, lesch-naphalene syndrome, kelley-seegmi syndrome, kidney disease, kidney stone, renal failure, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis, or hypoxanthine-guanine phosphoribosyltransferase deficiency, preferably gout or hyperuricemia.
The various compounds provided by the invention, and salts, hydrates, optical isomers, solvates, pharmaceutically acceptable salts or prodrugs thereof are selective uric acid reabsorption inhibitors, can treat hyperuricemia and gout by promoting the excretion of uric acid from the body and reducing serum uric acid, and have the effect of reducing uric acid in the bodies of animals and human bodies.
Furthermore, for the compounds of the present invention, isotopic substitutions thereof, such as deuterated, tritiated, and,14Generation C and15the N generation also has the same activity and utility. For example, isotopic substitutions can replace a hydrogen with deuterium and/or tritium. Also, the same applies toOf natural abundance12C can be covered13C or14C-substituted, naturally abundant14N can be covered15N substitution, natural abundance16O quilt17O or18O substitution, and the like or any combination.
In the present invention, said C1～C6Alkyl of (A) means C1、C2、C3、C4、C5、C6The alkyl group of (a), i.e., a straight-chain or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, tert-butyl, sec-butyl, tert-butylmethyl, and the like.
In the present invention, said C3～C6Cycloalkyl of (C) means C3、C4、C5、C6The cycloalkyl group of (a), i.e., a cycloalkyl group having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and the like.
As used herein, "pharmaceutically acceptable" means that the carrier, cargo, diluent, excipient, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising a pharmaceutical dosage form and is physiologically compatible with the recipient.
In the present invention, the "salt" is an acid and/or base salt of a compound or a stereoisomer thereof with an inorganic and/or organic acid and a base, and also includes a zwitterionic salt (inner salt), and also includes a quaternary ammonium salt such as an alkylammonium salt. These salts can be obtained directly in the final isolation and purification of the compounds. The compound, or a stereoisomer thereof, may be obtained by appropriately (e.g., equivalentlymixing) a certain amount of an acid or a base. These salts may form precipitates in the solution which are collected by filtration, or they may be recovered after evaporation of the solvent, or they may be prepared by reaction in an aqueous medium followed by lyophilization. The salt in the invention can be hydrochloride, sulfate, citrate, benzene sulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate of the compound, and can also be alkali metal ion salt such as sodium salt and potassium salt of the compound.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The reaction formula is as follows:
Figure BDA0001172277200000131
example 1
Figure BDA0001172277200000132
Synthesis of ethyl 2- (6-bromoquinoline-4-thio) -2-methylpropionate (intermediate 2)
Figure BDA0001172277200000133
6-bromo-4-chloroquinoline (2.42g, 10mmol), sodium sulfide (1.17g,15mmol) and N-methylpyrrolidone (30M L) were charged into a 100M L reaction flask, and the mixture was heated to 120 ℃ and stirred to react for 2 hours, and then cesium carbonate (6.52g,20mmol) and ethyl 2-bromoisobutyrate (2.15g,11mmol) were charged into the reaction flask, and the reaction was continued at 100 ℃ for 2 hours, after the completion of the reaction, water (150M L) was added, followed by extraction with ethyl acetate three times (3 × 100ml), and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and subjected to rotary evaporation to column chromatography to obtain intermediate 2(2.1g) at a yield of 60%. MS:354,356(M + H), and yield of 60% MS: 356(M + H)+)。
Synthesis of 2- (6-bromoquinoline-4-thio) -2-methylpropanoic acid (22)
Figure BDA0001172277200000141
The intermediate 2(354mg, 1mmol), methanol (5m L) and water (5m L) were added to a 100m L reaction flask and reacted at room temperature for 16 hours, after the reaction was completed, the reaction mixture was neutralized with 2N hydrochloric acid in an ice-water bath to a pH of about 5, and then filtered, the filter cake was washed with 10m L water and dried to obtain the compound 22(228mg) with a yield of 70%.1H NMR (400MHz, DMSO) (ppm)13.09(s,1H),8.89(d, J ═ 4.0Hz,1H),8.51(d, J ═ 4.0Hz,1H),7.96(M,2H),7.64(d, J ═ 4.0Hz,1H),1.55(s,6H) mass spectrum 326.1,328.1(M + H), mass spectrum+)。
The target products 23, 24, 83, 93, 94, 95, 96, 114, 128 and 129 are synthesized by the same method and corresponding reagents.
Figure BDA0001172277200000142
Product 23(2- (6-bromoquinoline-4-thio) -propionic acid): 312.0, 314.0(M + H)+)。
Figure BDA0001172277200000143
Product 24(2- (6-bromoquinoline-4-thio) -butyric acid):1h NMR (DMSO,400 MHz): (ppm)13.22(s,1H),8.81(d, J ═ 4.8Hz,1H),8.28(d, J ═ 1.2Hz,1H),7.99-7.94(m,2H),7.65(d, J ═ 4.8Hz,1H),4.29(t, J ═ 7.2Hz,1H),2.01-1.90(m,2H),1.06(t, J ═ 7.2Hz, 3H); mass spectrum: 325.9,327.9(M + H)+)。
Figure BDA0001172277200000144
Product 83(2- (6-bromoquinoline-4-thio) -2-ethylbutyric acid):1h NMR (DMSO,400 MHz): (ppm)13.09(s,1H),8.87(d, J ═ 4.0Hz,1H),8.56(d, J ═ 4.0Hz,1H),7.96(m,2H),7.61(d, J ═ 4.0Hz,1H),1.84-1.77(m,4H),0.92(t,6H) ms: 354.0,356.0(M + H)+)。
Figure BDA0001172277200000151
Product 93(2- (quinoline-4-thio) -2-methylpropionic acid):1H NMR(CDCl3400 MHz): (ppm)8.60(d, J ═ 4.0Hz,1H),8.35(d, J ═ 4.0Hz,1H),8.07(d, J ═ 4.0Hz,1H),7.65(m,2H),7.51(t, J ═ 4.0Hz,1H),1.81(t,6H) mass spectrometry: 324.1(M + H)+)。
Figure BDA0001172277200000152
Product 94(2- (6-bromoquinoline-4-thio) -3-methylbutyric acid):1h NMR (DMSO,400 MHz): (ppm)13.10(s,1H),8.79(d, J ═ 8.0Hz,1H),8.29(d, J ═ 4.0Hz,1H),7.96(m,2H),7.61(d, J ═ 8.0Hz,1H),4.13(d, J ═ 7.6Hz,1H),2.27-2.24(m,1H),1.14-1.10(t,6H) ms: 340.0,342.0(M + H)+)。
Figure BDA0001172277200000153
Product 95(2- (6, 7-dimethoxyquinoline-4-thio) -2-methylpropionic acid):1h NMR (DMSO,400 MHz): (ppm)8.62(d, J ═ 4.0Hz,1H),7.67(s,1H),7.45(d, J ═ 4.0Hz,1H),7.40(1H, s),3.94(6H, s),1.51(6H, s); mass spectrum: 308.1(M + H)+)。
Figure BDA0001172277200000154
Product 96(2- (6-trifluoromethylquinoline-4-thio) -2-methylpropionic acid):1h NMR (DMSO,400 MHz): (ppm)13.10(s,1H),8.96(d, J ═ 8.0Hz,1H),8.28(d, J ═ 4.0Hz,1H),8.05(m,2H),7.40(d, J ═ 8.0Hz,1H),1.5(s, 6H); mass spectrum: 316.0(M + H)+)。
Figure BDA0001172277200000161
Product 114(2- (6-bromoquinoline-4-thio) -2-propylpentanoic acid):1H NMR(DMSO,400MHz)：(ppm):8.84(d, J ═ 4.0Hz,1H),8.54(d, J ═ 4.0Hz,1H),7.94(m,2H),7.61(d, J ═ 4.0Hz,1H),1.78-1.65(m,4H),1.46-1.29(m,4H),0.89-0.82(m, 6H); mass spectrum: 381.9,383.9(M + H)+)。
Figure BDA0001172277200000162
Product 128(2- (6-trifluoromethyl-quinoline-4-thio) -2-propylpentanoic acid):1h NMR (DMSO,400 MHz): (ppm):13.01(s,1H),8.81(d, J ═ 4.0Hz,1H),8.47(d, J ═ 4.0Hz,1H),7.94(m,2H),7.59(d, J ═ 4.0Hz,1H),1.77-1.62(m,4H),1.45-1.27(m,4H),0.87-0.80(m, 6H); mass spectrum: 344.1(M + H)+)。
Figure BDA0001172277200000163
Product 129 (2-quinoline-4-thio) -2-propylpentanoic acid): mass spectrum: 276.1(M + H)+)
Example 2
Figure BDA0001172277200000164
(product 87) Synthesis
Adding intermediate 2(325mg,1mmol), dichloromethane (10M L) and DMF (20mg) into a 100M L reaction flask, adding oxalyl chloride (1g, 8mmol), heating to 40 ℃ for reaction for 1 hour, concentrating to dryness, adding dichloromethane (10M L), triethylamine (500mg,5mmol), 4-aminopyridine (190mg,2mmol), heating to 40 ℃ for reaction for 1 hour, adding water (50M L), extracting with ethyl acetate three times (3 × 50ml), combining organic layers, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, and performing rotary evaporation to obtain compound 87(160mg) with yield of 40%, MS:401.0,403.0(M + H) and MS:401.0,403.0(M + H)+).
The target products 88, 89, 90, 91 and 92 are synthesized by the same method and corresponding reagents.
Figure BDA0001172277200000171
Product 88(2- (6-bromoquinoline-4-thio) -2-methylpropionyl- (2-aminopyridine)): mass spectrum: 401.0,403.0(M + H)+)。
Figure BDA0001172277200000172
Product 89(2- (6-bromoquinoline-4-thio) -2-methylpropionyl- (3-aminopyridine)): mass spectrum: 401.0,403.0(M + H)+)。
Figure BDA0001172277200000173
Product 90(2- (quinoline-4-thio) -2-methylpropionyl- (4-aminopyridine)): mass spectrum: 324.1(M + H)+)。
Figure BDA0001172277200000174
Product 91(2- (quinoline-4-thio) -2-methylpropionyl- (2-aminopyridine)) ms spectrum: 324.1(M + H)+)。
Figure BDA0001172277200000175
Product 92(2- (quinoline-4-thio) -2-methylpropionyl- (3-aminopyridine)): mass spectrum: 324.1(M + H)+)。
Example 3
Figure BDA0001172277200000181
To a 50m L flask, intermediate A-1(112mg, 0.33mmol), cyclopropylsulfonamide (52mg, 0.43mmol), HATU (163mg, 0.43mmol), DIPEA (129mg, 1mmol), DMF (3m L) were added and the reaction stirred at room temperature for 16 hours after completion of the reaction, 20m L water was added followed by extraction with EA (15m L× 3), drying, and the crude product after spin-drying was purified with prep-HP L C to give compound 105(50mg) in 34% yield.1H NMR(400MHz,CDCl3)8.70(d,J＝4.6Hz，1H),8.23(d,J＝2.0Hz,1H),8.01(dJ8.8 Hz,1H),7.85(m,1H),6.95(d, J4.8 Hz,1H),3.18-3.10(m,2H),2.83-2.73(m,2H),2.42(dd, J11.2 Hz,2H),2.26-2.14(m,1H),1.18-1.12(m,2H),0.91-0.84(m,2H), ms: 440.8,442.8(M + H)+)
Compounds 106, 107 were prepared using the corresponding starting materials and the same preparative method as 105.
Figure BDA0001172277200000182
Product 1062- (6-bromoquinoline-4-thio) -N- (cyclopropylsulfonyl) -2-methylpropanamide 1H NMR (400MHz, CDCl)3)8.78(d, J ═ 4.7Hz,1H),8.41(d, J ═ 2.1Hz,1H),8.02(d, J ═ 8.9Hz,1H),7.85(m, 1H), 7.33(d, J ═ 4.6Hz,1H),2.98-2.90(m,2H),1.73(s,6H),2.26-2.14(m,1H),1.38-1.31(m, 2H); mass spectrum: 428.8,430.8(M + H)+)
Figure BDA0001172277200000183
Product 1071- (6-bromoquinoline-4-thio) -N- (methylsulfonyl) cyclobutylformamide, Mass Spectrometry: 414.8,416.8(M + H)+)。
Example 4
Figure BDA0001172277200000191
(intermediate 4) Synthesis
Figure BDA0001172277200000192
Adding the intermediate 3(241mg,1mmol), 2-methoxyphenylboronic acid (152mg,1mmol), sodium carbonate (212mg,2mmol), bis (diphenylphosphino) ferrocene palladium dichloride (37mg,0.05mmol), dioxane (6m L) and water (3m L) into a 50m L reaction flask, then replacing with nitrogen, heating to 110 ℃ under the protection of nitrogen for reaction for 2 hours, after the reaction is finished, adding water (50m L), extracting with ethyl acetate for three times (3 × 50ml), combining organic layers, washing with saturated common salt water, drying with anhydrous sodium sulfate, filtering, and performing rotary evaporation and then passing through a column to obtain the intermediate 4 (1) (1 mmol)90mg), yield 50%. Mass Spectrum 270.0,272.0(M + H)+)
(intermediate 5) Synthesis
Figure BDA0001172277200000193
Intermediate 4(2.69g,10mmol), sodium sulfide (1.17g,15mmol) and N-methylpyrrolidone (30M L) were charged into a 100M L reaction flask, and the mixture was heated and stirred to 120 ℃ to react for 2 hours, and then cesium carbonate (6.52g,20mmol) and ethyl 2-bromoisobutyrate (2.15g,11mmol) were charged into the reaction flask, and the reaction was continued at 100 ℃ for 2 hours, after the completion of the reaction, water (150M L) was added, extraction was carried out three times (3 × 100ml) with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and after rotary evaporation, intermediate 5(2.1g) was obtained by column chromatography in 60% yield, Mass Spectrometry: 382.0(M + H) (M + H ×)+)
(19) Synthesis of (2)
Figure BDA0001172277200000201
Adding the intermediate 5(381mg,1mmol), methanol (5M L) and water (5M L) into a reaction flask of 100M L, reacting for 16 hours at room temperature, neutralizing with 2N hydrochloric acid under the condition of ice-water bath until the pH is about 5, filtering, washing a filter cake with 10M L water, drying the filter cake to obtain a product 19(247mg) with the yield of 70%, and carrying out mass spectrum of 354.1(M + H)+)
Compound 1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 13; 14; 15; 16; 17; 18; 20; 21; 25; 26; 27; 28; 29; 30, of a nitrogen-containing gas; 31; 32, a first step of removing the first layer; 33; 34; 35; 36; 37; 38; 39; 40; 41; 42; 84; 85 parts by weight; 86; 100, respectively; 101, a first electrode and a second electrode; 102, and (b); 103; 104; 108; 109; 110; 111; 112, a first electrode; 113; 115, 115; 116; 117; 118; 119; 120 of a solvent; 121, a carrier; 122; 123; 124; 125; 126; 127; 138; 139; 140 of a solvent; 141, a solvent; 142 were synthesized in the same manner using the corresponding reagents.
Figure BDA0001172277200000202
Product 1(2- (6-cyclopropylquinoline-4-thio) -2-methylpropionic acid):1h NMR (400MHz, DMSO) (ppm)12.97(s,1H),8.72(d, J ═ 4.0Hz,1H),8.03(d, J ═ 4.0Hz,1H),7.93(d, J ═ 4.0Hz,1H),7.52-7.47(m,2H),2.20-2.09(m,1H),1.55(s,6H),1.10-1.02(m,2H),0.83-0.75(m,2H) mass spectrum: 288.1(M + H)+)。
Figure BDA0001172277200000203
Product 2(2- (6- (2-pyridine) -quinoline-4-thio) -2-methylpropionic acid): mass spectrum: 325.1(M + H)+)。
Figure BDA0001172277200000204
Product 3(2- (6- (3-pyridine) -quinoline-4-thio) -2-methylpropionic acid):1h NMR (400MHz, DMSO) (ppm)12.94(s,1H),9.04(d, J ═ 4.0Hz,1H),8.88(m,1H),8.66-8.62(m,2H),8.22-8.16(m,3H),7.66(d, J ═ 4.0Hz,1H),7.58(m,1H),1.58(s,6H) mass spectra: 325.1(M + H)+)。
Figure BDA0001172277200000211
Product 4(2- (6- (4-pyridine) -quinoline-4-thio) -2-methylpropionic acid):1h NMR (400MHz, DMSO) (ppm)13.00(s,1H),8.90(d, J ═ 4.0Hz,1H),8.74-8.70(m,3H),8.22-8.20(m,2H),7.86(m,2H),7.67(d, J ═ 4.0Hz,1H),1.58(s,6H) mass spectrum: 325.1(M + H)+)。
Figure BDA0001172277200000212
Product 5(2- (6-cyclopropylquinoline-4-thio) -propionic acid): mass spectrum: 274.1(M + H)+)。
Figure BDA0001172277200000213
Product 6(2- (6-cyclopropylquinoline-4-thio) -propionic acid): mass spectrum: 288.1(M + H)+)。
Figure BDA0001172277200000214
Product 7(2- (6- (2-pyridine) -quinoline-4-thio) -propionic acid): mass spectrum: 311.1(M + H)+)。
Figure BDA0001172277200000215
Product 8(2- (6- (2-pyridine) -quinoline-4-thio) -butyric acid): mass spectrum: 325.1(M + H)+)。
Figure BDA0001172277200000221
Product 9(2- (6- (3-pyridine) -quinoline-4-thio) -propionic acid): mass spectrum: 311.1(M + H)+)。
Figure BDA0001172277200000222
Product 10(2- (6- (3-pyridine) -quinoline-4-thio) -butyric acid): mass spectrum: 325.1(M + H)+)。
Figure BDA0001172277200000223
Product 11(2- (6- (4-pyridine) -quinoline-4-thio) -propionic acid): mass spectrum: 311.1(M + H)+)。
Figure BDA0001172277200000224
Product 12(2- (6- (4-pyridine) -quinoline-4-thio) -butyric acid): mass spectrum: 325.1(M + H)+)。
Figure BDA0001172277200000225
Product 13(2- (6- (2-methoxyphenyl) -quinoline-4-thio) -propionic acid): mass spectrum: 340.1(M + H)+)。
Figure BDA0001172277200000226
Product 14(2- (6- (2-methoxyphenyl) -quinolin-4-thio) -butyric acid): mass spectrum: 354.1(M + H)+)。
Figure BDA0001172277200000231
Product 15(2- (6- (3-methoxyphenyl) -quinoline-4-thio) -propionic acid): mass spectrum: 340.1(M + H)+)。
Figure BDA0001172277200000232
Product 16(2- (6- (3-methoxyphenyl) -quinolin-4-thio) -butyric acid): mass spectrum: 354.1(M + H)+)。
Figure BDA0001172277200000233
Product 17(2- (6- (4-methoxyphenyl) -quinoline-4-thio) -propionic acid): mass spectrum: 340.1(M + H)+)。
Figure BDA0001172277200000234
Product 18(2- (6- (4-methoxyphenyl) -quinolin-4-thio) -butyric acid): mass spectrum: 354.1(M + H)+)。
Figure BDA0001172277200000235
Product 19(2- (6- (2-methoxyphenyl) -quinoline-4-thio) -2-methylpropionic acid):1h NMR (DMSO,400 MHz): (ppm)12.98(s,1H),8.84(d, J ═ 4.0Hz,1H),8.43(d, J ═ 4.0Hz,1H),8.06(d, J ═ 4.0Hz,1H),7.95(m,1H),7.58(d, J ═ 4.0Hz,1H),7.44-7.41(m,2H),7.19(d, J ═ 4.0Hz,1H),7.13-7.09(m,1H),3.87(s,3H),1.56(s, 6H); mass spectrum: 354.1(M + H)+)。
Figure BDA0001172277200000236
Product 20(2- (6- (3-methoxyphenyl) -quinoline-4-thio) -2-methylpropionic acid):1h NMR (DMSO,400 MHz): (ppm)8.92(d, J ═ 4.9Hz,1H),8.55(d, J ═ 1.8Hz,1H),8.22(dt, J ═ 22.3,5.3Hz,2H),7.67(d, J ═ 4.9Hz,1H),7.49(t, J ═ 7.9Hz,1H),7.42-7.31(m,2H),7.05(dd, J ═ 8.1,1.8Hz,1H),3.87(s,3H),1.64(s, 6H); mass spectrum: 354.1(M + H)+)。
Figure BDA0001172277200000241
Product 21(2- (6- (4-methoxyphenyl) -quinoline-4-thio) -2-methylpropionic acid):1h NMR (DMSO,400 MHz): (ppm)12.99(s,1H),8.81(d, J ═ 4.0Hz,1H),8.51(d, J ═ 4.0Hz,1H),8.10(m,2H),7.77(d, J ═ 4.0Hz,2H),7.60(d, J ═ 4.0Hz,1H),7.11(d, J ═ 4.0Hz,2H),3.84(s,3H),1.57(s, 6H); mass spectrum: 354.1(M + H)+)。
Figure BDA0001172277200000242
Product 25(2- (6- (2-fluoro-phenyl) -quinoline-4-thio) -2-methylpropionic acid):1h NMR (DMSO,400 MHz): (ppm)13.02(s,1H),8.88(d, J ═ 4.0Hz,1H),8.52(d, J ═ 4.0Hz,1H),8.15(d, J ═ 8.0Hz,1H),8.02-8.0(m,1H),8.00-7.99(m,1H),7.72(d, J ═ 8.0Hz,1H),7.54-7.49(m,1H),7.43-7.38(m,2H),1.57(s, 6H); mass spectrum: 342.0(M + H)+)。
Figure BDA0001172277200000243
Product 26(2- (6- (2-fluoro-phenyl) -quinoline-4-thio) -propionic acid) Mass Spectrometry: 328.0(M + H)+)。
Figure BDA0001172277200000244
Product 27(2- (6- (2-fluoro-phenyl) -quinolin-4-thio) -butyric acid) mass spectrum: 342.0(M + H)+)。
Figure BDA0001172277200000251
Product 28(2- (6- (3-fluoro-phenyl) -quinoline-4-thio) -2-methylpropionic acid):1h NMR (DMSO,400 MHz): (ppm)12.97(s,1H),8.87(d, J ═ 8.0Hz,1H),8.59(s,1H),8.18-8.13(m,2H),7.69-7.60(m,4H),7.32-7.27(m,1H),1.58(s, 6H); mass spectrum: 342.0(M + H)+)。
Figure BDA0001172277200000252
Product 29(2- (6- (3-fluoro-phenyl) -quinoline-4-thio) -propionic acid), ms spectrum: 328.0(M + H)+)。
Figure BDA0001172277200000253
Product 30(2- (6- (3-fluoro-phenyl) -quinolin-4-thio) -butyric acid) mass spectrum: 342.0(M + H)+)。
Figure BDA0001172277200000254
Product 31(2- (6- (4-fluoro-phenyl) -quinoline-4-thio) -2-methylpropionic acid) Mass Spectrometry: 342.0(M + H)+)。
Figure BDA0001172277200000255
Product 32(2- (6- (4-fluoro-phenyl) -quinoline-4-thio) -propionic acid) Mass Spectrometry: 328.0(M + H)+)。
Figure BDA0001172277200000256
Product 33(2- (6- (4-fluoro-phenyl) -quinolin-4-thio) -butyric acid) mass spectrum: 342.0(M + H)+)。
Figure BDA0001172277200000261
Product 34(2- (6- (4-trifluoromethyl-phenyl) -quinoline-4-thio) -2-methylpropionic acid):1h NMR (DMSO,400 MHz): (ppm)12.98(s,1H),8.89(d, J ═ 4.0Hz,1H),8.64(s,1H),8.19(d, J ═ 4.0Hz,2H),8.06(d, J ═ 4.0Hz,2H),7.91(d, J ═ 4.0Hz,2H),7.66(d, J ═ 4.0Hz,1H),1.57(s, 6H); mass spectrum: 392.0(M + H)+)。
Figure BDA0001172277200000262
Product 35(2- (6- (4-trifluoromethyl-phenyl) -quinoline-4-thio) -propionic acid) Mass Spectrometry: 378.0(M + H)+)。
Figure BDA0001172277200000263
Product 36(2- (6- (4-trifluoromethyl-phenyl) -quinoline-4-thio) -butyric acid) mass spectrum: 392.0(M + H)+)。
Figure BDA0001172277200000264
Product 37(2- (6- (2-trifluoromethyl-phenyl) -quinoline-4-thio) -2-methylpropionic acid):1h NMR (DMSO,400 MHz): (ppm)13.02(s,1H),8.89(d, J ═ 4.0Hz,1H),8.25(d, J ═ 4.0Hz,1H),8.12(d, J ═ 8.0Hz,1H),7.91(d, J ═ 4.0Hz,1H),7.78-7.70(m,3H),7.61-7.55(m,2H),1.53(s, 6H); mass spectrum: 392.0(M + H)+)。
Figure BDA0001172277200000265
Product 38(2- (6- (2-trifluoromethyl-phenyl) -quinoline-4-thio) -propionic acid) Mass Spectrometry: 378.0(M + H)+)。
Figure BDA0001172277200000271
Product 39(2- (6- (2-trifluoromethyl-phenyl) -quinoline-4-thio) -butyric acid) Mass Spectrometry: 392.0(M + H)+)。
Figure BDA0001172277200000272
Product 40(2- (6- (3-trifluoromethyl-phenyl) -quinoline-4-thio) -2-methylpropionic acid) Mass Spectrometry: 392.0(M + H)+)。
Figure BDA0001172277200000273
Product 41(2- (6- (3-trifluoromethyl-phenyl) -quinoline-4-thio) -propionic acid) Mass Spectrometry: 378.0(M + H)+)。
Figure BDA0001172277200000274
Product 42(2- (6- (3-trifluoromethyl-phenyl) -quinoline-4-thio) -butyric acid) mass spectrum: 392.0(M + H)+)。
Figure BDA0001172277200000275
Product 84(2- (6- (3, 4-dimethoxy-phenyl) -quinoline-4-thio) -2-methylpropionic acid) Mass Spectrometry: 384.0(M + H)+)。
Figure BDA0001172277200000276
Product 85(2- (6- (3, 4-dimethoxy-phenyl) -quinoline-4-thio) -2-ethylbutyric acid) Mass Spectrometry: 412.0(M + H)+)。
Figure BDA0001172277200000281
Product 86(2- (6-cyclopropylquinoline-4-thio) -2-ethylbutyric acid) Mass Spectrometry: 316.0(M + H)+)。
Figure BDA0001172277200000282
Product 100(2- (6- (4-cyano-phenyl) -quinoline-4-thio) -2-methylpropionic acid) Mass Spectrometry: 349.0(M + H)+)。
Figure BDA0001172277200000283
Product 101(2- (6- (3-trifluoromethoxy-phenyl) -quinoline-4-thio) -2-methylpropionic acid) Mass Spectrometry: 408.0(M + H)+)。
Figure BDA0001172277200000284
Product 102(2- (6- (3-ethoxy-phenyl) -quinoline-4-thio) -2-methylpropionic acid) Mass Spectrometry: 368.0(M + H)+)。
Figure BDA0001172277200000285
Product 103(2- (6- (3-isopropoxy-phenyl) -quinoline-4-thio) -2-methylpropionic acid) mass spectrum: 382.0(M + H)+)。
Figure BDA0001172277200000286
Product 104(2- (6- (3-difluoromethoxy-phenyl) -quinoline-4-thio) -2-methylpropionic acid) Mass Spectrometry: 390.0(M + H)+)。
Figure BDA0001172277200000291
Product 108(2- (6- (3-ethoxy-phenyl) -quinolin-4-thio) -2-propylpentanoic acid) Mass Spectrometry: 424.1(M + H)+)。
Figure BDA0001172277200000292
Product 109(2- (6- (3-cyclopropyloxy-phenyl) -quinoline-4-thio) -2-propylpentanoic acid) Mass Spectrometry: 436.1(M + H)+)。
Figure BDA0001172277200000293
Product 110(2- (6- (3-cyclobutane)Aryloxy-phenyl) -quinoline-4-thio) -2-propylpentanoic acid) mass spectrum: 450.1(M + H)+)。
Figure BDA0001172277200000294
Product 111(2- (6- (3-cyclobutyloxy-phenyl) -quinoline-4-thio) -2-ethylbutyric acid) Mass Spectrometry: 422.1(M + H)+)。
Figure BDA0001172277200000295
Product 112(2- (6- (3-cyclopropyloxy-phenyl) -quinoline-4-thio) -2-ethylbutyric acid) Mass Spectrometry: 408.1(M + H)+)。
Figure BDA0001172277200000296
Product 113(2- (6- (3-ethoxy-phenyl) -quinolin-4-thio) -2-ethylbutyric acid) Mass Spectrometry: 396.1(M + H)+)。
Figure BDA0001172277200000301
Product 115(2- (6- (2-methoxypyridin-4-) -quinolin-4-thio) -2-methylpropionic acid):1h NMR (DMSO,400 MHz): (ppm):13.02(s,1H),8.95(d, J ═ 4.0Hz,1H),8.77(d, J ═ 4.0Hz,1H),8.36(d, J ═ 4.0Hz,1H),8.20(m,2H),7.66(d, J ═ 4.0Hz,1H),7.47(m,1H),7.24(s,1H),3.94(s,3H),0.95-0.85(m, 6H); mass spectrum: 355.1(M + H)+)。
Figure BDA0001172277200000302
Product 116(2- (6- (2-methoxypyridin-4-) -quinolin-4-thio) -2-ethylbutyric acid):1h NMR (DMSO,400 MHz): (ppm):12.96(s,1H),8.87(d, J ═ 4.0Hz,1H),8.74(d, J ═ 4.0Hz,1H),8.33(d, J ═ 4.0Hz,1H),8.18(m,2H),7.64(d, J ═ 4.0Hz,1H),7.44(m,1H),7.24(s,1H),3.94(s,3H),1.91-1.82(m,4H),0.95-0.85(m, 6H); mass spectrum: 383.2(M + H)+)。
Figure BDA0001172277200000303
Product 117(2- (6- (2-fluoropyridin-4-) -quinolin-4-thio) -2-methylpropionic acid):1h NMR (DMSO,400 MHz): (ppm):13.02(s,1H),8.95(d, J ═ 4.0Hz,1H),8.77(d, J ═ 4.0Hz,1H),8.36(d, J ═ 4.0Hz,1H),8.20(m,2H),7.66(d, J ═ 4.0Hz,1H),7.47(m,1H),7.24(s,1H),0.93(m, 6H); mass spectrum: 343.0(M + H)+)。
Figure BDA0001172277200000304
Product 118(2- (6- (2-fluoropyridin-4-) -quinolin-4-thio) -2-ethylbutyric acid):1h NMR (DMSO,400 MHz): (ppm):12.96(s,1H),8.87(d, J ═ 4.0Hz,1H),8.74(d, J ═ 4.0Hz,1H),8.33(d, J ═ 4.0Hz,1H),8.18(m,2H),7.64(d, J ═ 4.0Hz,1H),7.44(m,1H),7.24(s,1H),3.94(s,3H),1.89(m,4H),0.91(m, 6H); mass spectrum: 371.0(M + H)+)。
Figure BDA0001172277200000311
Product 119(2- (6- (pyridine-4-) -quinoline-4-thio) -2-ethylbutyric acid):1h NMR (DMSO,400 MHz): (ppm):13.00(s,1H),8.90(d, J ═ 8.0Hz,1H),8.72(m,3H),8.21(m,2H),7.86(m,2H),7.67(d, J ═ 4.0Hz,1H),1.93(m,4H),1.58(m, 6H); mass spectrum: 353.1(M + H)+)。
Figure BDA0001172277200000312
Product 120(2- (6- (2-methylpyridin-4-) -quinoline-4-thio) -2-methylpropionic acid): 13.03(s,1H),8.87(d, J ═ 4.0Hz,1H),8.74(d, J ═ 4.0Hz,1H),8.33(d, J ═ 4.0Hz,1H),8.18(m,2H),7.64(d, J ═ 4.0Hz,1H),7.44(m,1H),7.24(s,1H),2.71(s,3H),1.52(m, 6H); mass spectrum: 339.1(M + H)+)。
Figure BDA0001172277200000313
Product 121(2- (6- (2-methylpyridin-4-) -quinoline-4-thio) -2-ethylbutyric acid):1h NMR (DMSO,400 MHz): (ppm):12.99(s,1H),8.85(d, J ═ 4.0Hz,1H),8.77(d, J ═ 4.0Hz,1H),8.35(d, J ═ 4.0Hz,1H),8.15(m,2H),7.69(d, J ═ 4.0Hz,1H),7.47(m,1H),7.26(s,1H),3.94(s,3H),1.92(m,4H),0.9(m, 6H); mass spectrum: 367.1(M + H)+)。
Figure BDA0001172277200000314
Product 122(2- (6- (3-fluoropyridin-4-) -quinolin-4-thio) -2-methylpropionic acid) mass spectrum: 343.1(M + H)+)。
Figure BDA0001172277200000315
Product 123(2- (6- (3-fluoropyridin-4-) -quinolin-4-thio) -2-ethylbutyric acid) mass spectrum: 371.1(M + H)+)。
Figure BDA0001172277200000321
Product 124(2- (6- (3-chloropyridin-4-) -quinolin-4-thio) -2-methylpropionic acid) mass spectrum: 359.0(M + H)+)。
Figure BDA0001172277200000322
Product 125(2- (6- (3-chloropyridin-4-) -quinolin-4-thio) -2-ethylbutyric acid) mass spectrum: 387.0(M + H)+)。
Figure BDA0001172277200000323
Product 126(2- (6- (2-hydroxypyridine-4-) -quinoline-4-thio) -2-ethylbutyric acid) mass spectrum: 369.0(M + H)+)。
Figure BDA0001172277200000324
Product 127(2- (6- (1-)Methyl-2-oxo-1, 2-dihydropyridin-4-) -quinoline-4-thio) -2-ethylbutyric acid) mass spectrum: 383.0(M + H)+)。
Figure BDA0001172277200000325
Product 138(2- (6- (3-cyano-phenyl) -quinoline-4-thio) -2-ethylbutyric acid) Mass Spectrometry: 377.1(M + H)+)。
Figure BDA0001172277200000326
Product 139(2- (6- (3-trifluoromethyl-phenyl) -quinoline-4-thio) -2-ethylbutyric acid) Mass Spectrometry: 420.1(M + H)+)。
Figure BDA0001172277200000331
Product 140(2- (6- (3-fluoro-phenyl) -quinolin-4-thio) -2-ethylbutyric acid) Mass Spectrometry: 370.1(M + H)+)。
Figure BDA0001172277200000332
Product 141(2- (6- (2-fluoro-phenyl) -quinolin-4-thio) -2-ethylbutyric acid) Mass Spectrometry: 370.1(M + H)+)。
Figure BDA0001172277200000333
Product 142(2- (6- (4-fluoro-phenyl) -quinolin-4-thio) -2-ethylbutyric acid) Mass Spectrometry: 370.1(M + H)+)。
EXAMPLE 2 biological assays of Compounds of the invention
Test example: determination of the inhibitory Activity of the Compounds of the invention on URAT1
Experimental materials:
Figure BDA0001172277200000335
FBS(Invitrogen,Cat.No.10099141)
Figure BDA0001172277200000336
Trypsin(Invitrogen,Cat.No.25200056)
Figure BDA0001172277200000337
DPBS(Invitrogen,Cat.No.14190250)
Figure BDA0001172277200000338
DMEM(Invitrogen,Cat.No.10564)
Figure BDA0001172277200000339
Penicillin-Streptomycin(Invitrogen,Cat.No.15070-063)
Figure BDA00011722772000003310
TransIT-293Transfection Reagent(MIRUS BIO,Cat.No.MIR2706)
Figure BDA00011722772000003311
Figure BDA0001172277200000334
I Reduced Serum Medium(Invitrogen,Cat.No.31985-070)
Figure BDA00011722772000003312
URAT1plasmid(Genecopoeia,Cat.No.EX-T4563-M03)
Figure BDA00011722772000003313
Uric acid[8-14C](ARC,Cat.No.ARC0513-250UCI)
Figure BDA00011722772000003314
Ultima GoldTMXR(PerkinElmer,Cat.No.6013111)
Figure BDA0001172277200000342
benzbromorarone (Bailingwei science and technology, Cat. No.3562-84-3)
Figure BDA0001172277200000343
D-Gluconic acid sodium salt (Aladdin, Cat. No.527-07-1)
Figure BDA0001172277200000344
Potasssium D-gluconate (Aladdin, Cat. No.299-27-4)
Figure BDA0001172277200000345
Calcium gluconate (Aladdin. Cat. No.299-28-5)
Figure BDA0001172277200000346
DMSO(Sigma,Cat.No.D2650)
Figure BDA0001172277200000347
Tube,15ml(Greiner,Cat.No.07030115)
Figure BDA0001172277200000348
Tube,50ml(BD Falcon,Cat.No.352098)
Figure BDA0001172277200000349
Poly-D-lysine 96-well microplates(BD,Cat.No.356461)
Figure BDA00011722772000003410
Isoplate-96Microplate(PERKIN ELMER,Cat.No.6005040)
The experimental method comprises the following steps:
buffer solution preparation
Figure BDA0001172277200000341
Cell culture:
1. HEK-293T cells stably expressing hURAT1 were cultured in 10% FBS and 1% P/S DMEM medium overnight in a 37 ℃ incubator with 5% carbon dioxide.
2. The medium was removed and washed once with PBS, then trypsinized for 2 minutes, and 10 ml of medium was added to stop the digestion after the cells were separated on the petri dish.
3. The cells were placed in a centrifuge 1000 for 2 minutes, fresh 10 ml of medium was added to resuspend the cells, and the number of cells was counted. Cell number was adjusted to 4X105Per ml of individual cells.
4. The above counted cells were seeded into 96-well plates at 100. mu.l per well.
5. The 96-well plate inoculated with the cells was placed in a 37-degree cell incubator for overnight culture.
Isotope carbon 14-labeled uric acid absorption experiment:
1.5 ml of Cl-free HBSS buffer solution is added into a 15 ml centrifuge tube, and then carbon 14 labeled uric acid is added to make the concentration of the uric acid reach 2uCi/ml.
2. The medium in the 96-well plate previously incubated overnight was blotted dry and washed three times with 100ml of pre-warmed Cl-freeHBSS buffer.
3. The washed 96-well plate is then washed and the buffer solution is then aspirated.
4. 50 μ l of Cl-free HBSS buffer containing carbon-14 labeled uric acid was added to each well of the washed 96-well plate, followed by addition of a DMSO solution of the compound to be tested.
5. After the 96-well plate was allowed to stand at room temperature for 5 minutes, all the liquid in the plate was blotted.
6. Washed three times by adding 100ml of pre-cooled Cl-free HBSS buffer.
7. After the plate was blotted clean, 50 microliters of cell lysate was added to each well and shaken on a shaker at 600 rpm for 10 minutes.
8. Adding 50 muUtima GoldTMAfter XR sensitization cocktail scintillation, shaking was continued for 10 minutes. The well-shaken plates were mounted on a sealing plate film and read on a Microbeta Trilux.
9. Test compounds were dissolved in DMSO and then the same concentration of DMSO was added to HEK 293/haurat 1 cell wells that did not contain test compounds. Uric acid uptake by cells at each tested concentration was expressed as the average percent inhibition relative to DMSO control. The radioactivity values obtained for wells containing DMSO were taken as 100% uptake by the cells. IC50 values for compounds were calculated from inhibition at different concentrations.
The results for IC50(nM) inhibition of activity of compounds of the invention against hauat 1 are shown in table 1. Reference compound 1 was synthesized, among others, according to the method described in patent WO 2011/159839a 2. Reference compound 2 and reference compound 3 were synthesized according to the methods described in patent WO2014/183555a1 and tested head-to-head under equivalent conditions with compounds 83 and 129, respectively. IC50 for reference compounds 2 and 83 is the average of multiple head-to-head comparative experiments. The IC50 for reference compounds 3 and 129 is the average of two comparative experiments.
TABLE 1
Figure BDA0001172277200000361
Figure BDA0001172277200000371
From the above table, it can be found that the compound of the present invention has a significant inhibitory effect on uric acid transporter URAT 1.
Reference compounds 1 and 2 are known highly active uric acid transporter URAT1 inhibitors. Compound 83 exhibited better uric acid transporter inhibitory activity than reference compound 1. Meanwhile, statistical analysis of the data of the multiple head-to-head activity assays of compound 83 and reference compound 2 is shown in table 2, and the results demonstrate that the activity of compound 83 is significantly different from the activity data of reference compound 2. Compared with the structure and the activity of a reference compound 3, the combined compound 129 obviously improves the inhibitory activity of a uric acid transporter URAT1 of the compound after the cycloalkyl substitution of the compound at a specific position is changed into the open-loop alkyl substitution, particularly the diethyl substitution.
TABLE 2
Figure BDA0001172277200000381
The various compounds provided by the invention and salts, hydrates or solvates thereof are selective uric acid reabsorption inhibitors with higher biological activity than the typical compounds in the field, and can treat or prevent diseases characterized by uric acid level abnormality by promoting the excretion of uric acid from the body and reducing serum uric acid. Wherein the condition is selected from gout, recurrent gout attacks, hyperuricemia, cardiovascular disease, Lei-Naphthalein syndrome, Kai-Sedi syndrome, nephropathy, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis, or hypoxanthine-guanine phosphoribosyltransferase deficiency, and has uric acid lowering effects in animals and humans.

Claims (10)

1. A compound represented by the formula (I), or an optical isomer thereof, or a pharmaceutically acceptable salt thereof,
Figure FDA0002399011770000011
wherein R is1Selected from pyridyl, trifluoromethyl or Br;
R2and R3Are all selected from methyl; or, R2And R3Are all selected from ethyl;
R4is hydrogen.
2. The compound according to claim 1, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein: pharmaceutically acceptable salts thereof include salts with bases; also included are salts with pharmaceutically acceptable acids.
3. The compound according to claim 2, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein: the pharmaceutically acceptable salt thereof is a sodium salt.
4. The compound of claim 1, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, having a structure according to formula (Id):
Figure FDA0002399011770000012
wherein R is1Selected from pyridyl, trifluoromethyl or Br.
5. The following compound, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, the compound being one of the following compounds:
Figure FDA0002399011770000013
Figure FDA0002399011770000021
6. a process for the preparation of a compound according to any one of claims 1 to 5, characterized in that: comprises the following steps:
Figure FDA0002399011770000022
or, the method comprises the following steps:
Figure FDA0002399011770000023
7. use of a compound of any one of claims 1-5, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament of the URAT1 inhibitor class.
8. The use according to claim 7, which is a medicament for the prophylaxis and/or treatment of gout, hyperuricemia, hypertension, cardiovascular diseases, coronary heart disease, lesch-napharynl syndrome, keley-seegmy syndrome, nephropathy, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis or hypoxanthine-guanine phosphoribosyltransferase deficiency.
9. The use according to claim 8, wherein the medicament is a medicament for the prophylaxis and/or treatment of recurrent gout attacks, kidney stones, kidney failure, gouty arthritis.
10. Use according to claim 8, characterized in that: the medicine is a medicine for preventing and/or treating gout or hyperuricemia.
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RU2018120242A3 (en) 2020-01-09
RU2018120242A (en) 2020-01-09
AU2016368240A1 (en) 2018-06-28
DK3388420T3 (en) 2022-09-26
JP6752888B2 (en) 2020-09-09
WO2017097182A1 (en) 2017-06-15
EP3388420A4 (en) 2019-05-22
TW201720797A (en) 2017-06-16
CN106831570B (en) 2020-03-31
ES2926781T3 (en) 2022-10-28
EP3388420A1 (en) 2018-10-17
AU2016368240B2 (en) 2020-01-02
US10450274B2 (en) 2019-10-22
RU2715229C2 (en) 2020-02-26

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